A major regulator of body composition, energy balance and food intake is leptin, an adipocytokine [1]. Leptin circulates and has direct actions in the brain [2] and skeletal muscle [3, 4] by binding to the B isoform of leptin receptor (LEPR-B). Loss of leptin signaling also leads to hypothalamic hypogonadism and infertility. There are numerous hypothalamic nuclei that are responsive to leptin and each of these nuclei has numerous types of neurons, as defined by their neurotransmitter content [5, 6]. There are numerous lines of evidence which indicate leptin responsive neurons within the arcuate nucleus affect gonadotropin release. The orexigenic neuropeptides NPY [7, 8] and AGRP [9] have been shown to inhibit LH release. There are anatomical projections of arcuate nucleus neurons from NPY/AGRP neurons and from POMC (endorphin projections) [10] neurons to the medial preoptic area containing GnRH neurons [11]. Nevertheless, the functional impact of melanocortin modulation of GnRH neurons is not well characterized. We present preliminary data to suggest that melanocortin signaling is important to sexual development and reproductive competence within the context of leptin signaling deficiencies. We propose to study the role of melanocortinergic transmission in modulating GnRH neurons and reproductive function. The goals of this proposal are to examine the functional importance of melanocortinergic transmission in mediating the effects of leptin on GnRH neuronal function and reproductive competence. We have four specific aims that address the roles of leptin-regulated neuronal cell types in the regulation of the reproductive system. Aim 1. Determine the reproductive competence of mice with combined MC4R and LEPR deficiencies Aim 2, Determine the direct and indirect effects of melanocortins on GnRH neurons Aim 3. Determine the reproductive competence of increased melanocortinergic transmission in females with leptin receptor deficiency Aim 4. Determine the impact of restoring MC4R expression on GnRH neurons in females with combined MC4R and LEPR deficiencies